Epothilones are 16 member cyclic macrolide molecules which find utility in the pharmaceutical field. For example, Epothilone A and B are naturally occurring compounds that can be isolated from certain microorganisms; these two compounds have the following structures:                 Epothilone A R=H        Epothilone B R=Me        
Since the introduction of epothilones into the art, many groups have been designing, synthesizing and testing analogs of the naturally occurring epothilones in an attempt to develop useful pharmaceuticals. (See, e.g., D. Schinzer et al., Angew. Chem. Int. Ed. Engl., 1997, 36, No. 3, 523-524; K. C. Nicolaou, et al., J. Amer. Chem. Soc., 1997, 119, 7974-7991; K. C. Nicaloau et al., Angew. Chem. Int. Ed. Engl., 1996, 35, No. 20, 2399-2401; A. Balog et al., Angew. Chem. Int. Ed. Engl., 1996, 35, No. 23/24, 2801-2803).
Known epothilones exert microtubule-stabilizing effects similar to Taxol® and therefore exhibit cytotoxic activity against rapidly proliferating cells, such as occur in cancer and other hyperproliferative cellular diseases (See Angew. Chem. Int. Ed. Engl., Vol. 35, No. 13/14, 1996 and D. M. Bollag, Exp. Opin. Invest. Drugs, 6(7): 867-873, 1997).
Before epothilones can be used to treat diseases in patients, however, they must be formulated into a pharmaceutical composition that can be administered to the patient; for example, into a dosage form suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), or transdermal administration. Formulations for oral administration are particularly preferred since they are more convenient and easier to administer than other formulations. Also, the oral route of administration avoids the pain and discomfort of parenteral administration. Accordingly, formulations for oral administration are preferred by patients and result in better patient compliance with dosing schedules.
The usefulness of an oral formulation, however, requires that the active agent be bioavailable. Bioavailability of orally administered drugs is affected by various factors including, for example, drug absorption throughout the gastrointestinal tract, stability of the drug in the gastrointestinal tract, and the first pass effect. Thus, effective oral delivery of an active agent requires that the active agent have sufficient stability in the stomach and intestinal lumen to pass through the intestinal wall. Many drugs, however, tend to degrade quickly in the intestinal tract or have poor absorption in the intestinal tract so that oral administration is not an effective method for administering the drug.
Pharmaceutical compositions intended for oral administration are typically solid dosage forms (e.g., tablets) or liquid preparations (e.g., solutions, suspensions, or elixirs). Solid dosage forms, however, can impose restrictions on the pharmaceutical use of the active agent since some patient populations have difficulty, either physical or psychological, in swallowing solid oral dosage forms. If a liquid dosage form is available, these patients could more easily take the required dose of active ingredient by having it administered in the form of an oral liquid preparation that they can drink or having it administered, for example, by a naso-gastric tube. Thus, liquid oral dosage forms are desirable.
Liquid oral pharmaceutical compositions require a suitable solvent or carrier system to dissolve or disperse the active agent to enable the composition to be administered to a patient. The solvent system must be compatible with the active agent and be non-toxic to the patient. Commonly, the solvent for liquid oral formulations is a water based solvent.
The formulation of certain epothilones presents difficulties in addition to the normal hurdles, in that certain epothilones are either or both acid labile and/or poorly soluble in aqueous media, which is the media of first choice for oral solutions. The present invention, however, overcomes these difficulties and provides methods and pharmaceutical formulations for the oral administration of epothilones wherein the epothilones are sufficiently bioavailable to have a pharmacological effect.